Identification of Somatic Mutations in EGFR/KRAS/ALK-Negative Lung Adenocarcinoma

Supplemental Information

Identification of Somatic Mutations in EGFR/KRAS/ALK-negative Lung Adenocarcinoma inNever-Smokers

Jin Woo Ahn,1* Han Sang Kim,2,3* Jung-Ki Yoon,4,5* Hoon Jang,1 Soo Min Han,2Sungho Eun,6Hyo Sup Shim,7Hyun-Jung Kim,8Dae Joon Kim,9 Jin Gu Lee,9 Chang Young Lee,9 Mi Kyung Bae,9 Kyung Young Chung,9Ji Ye Jung,10 Eun Young Kim,10 Se Kyu Kim,10 Joon Chang,10Hye Ryun Kim,3 Joo Hang Kim,3 Min Goo Lee,2Byoung ChulCho,3$ Ji Hyun Lee,11$ Duhee Bang1$

Authors’Affiliations

1Department of Chemistry, Yonsei University, Seoul 120-752, Korea

2Department of Pharmacology, Pharmacogenomic Research Center for Membrane Transporters, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea

3Yonsei Cancer Center, Division of Medical Oncology, Department of internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea

4College of Medicine, Seoul National University, Seoul 110-799, Korea

5Hwasung Public Health Center, Hwasung, Korea

6College of Medicine, Yonsei University, Seoul 120-752, Korea

7Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Korea

8JE UK Institute for Cancer Research, Gumi City, Kyungbuk, Korea

9Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea

10Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

11Department of Oral Biology, College of Dentistry, Yonsei University, Seoul, Republic of Korea

1

Table of Contents

1. Supplemental Figures

Figure S1. Analysis flow chartforexomesequencing data...... 3

2.Supplemental Tables

Table S1. Summary of depth and coverage of whole exome sequencing...... 4

Table S2. Summary of depth and coverage in target capture sequencing for validation 5

Table S3. Validation results using target capture sequencing and Sanger sequencing 6

Table S4. Summary of validated somatic exonic mutations in EGFR/KRAS/ALK-negative lung adenocarcinomas 9

Table S5. Somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma exomes 10

Table S6. Mutated genes and loci information in EGFR/KRAS-negative lung adenocarcinoma 17

Table S7. Sequences of molecular inversion probes (MIPs)...... 20

Table S8. Sequences of primers used for Sanger sequencing...... 21

3. References for exome analysis...... 22

Figure S1.Analysis flow chart for exomesequencing data

1

Table S1.Summary of depth and coverage of whole exome sequencing

Sample / Depth of Coverage / 1× (%) / 5× (%) / 10× (%) / 15× (%) / 20× (%)
TNA#1 / Tumor / 54.81 / 94.52 / 91.17 / 87.87 / 84.29 / 80.37
Normal / 47.64 / 94.39 / 90.56 / 86.56 / 82.18 / 77.36
TNA#2 / Tumor / 76.91 / 93.81 / 91.27 / 89.46 / 87.74 / 85.91
Normal / 61.43 / 93.82 / 90.79 / 88.35 / 85.90 / 83.17
TNA#3 / Tumor / 36.83 / 92.95 / 88.41 / 83.33 / 77.38 / 70.54
Normal / 49.41 / 93.17 / 89.56 / 86.25 / 82.74 / 78.69
TNA#4 / Tumor / 64.25 / 92.68 / 89.16 / 86.05 / 82.83 / 79.35
Normal / 58.71 / 93.46 / 89.97 / 86.59 / 82.94 / 78.95
TNA#5 / Tumor / 36.83 / 94.55 / 89.37 / 75.95 / 68.85 / 54.91
Normal / 59.14 / 94.68 / 91.74 / 85.36 / 81.78 / 73.87
TNA#6 / Tumor / 72.82 / 94.95 / 91.62 / 84.84 / 81.36 / 74.18
Normal / 42.17 / 94.15 / 89.11 / 77.08 / 70.92 / 59.10
TNA#7 / Tumor / 37.60 / 94.42 / 89.40 / 76.69 / 69.93 / 56.43
Normal / 30.70 / 94.36 / 88.61 / 72.48 / 63.68 / 46.23
TNA#8 / Tumor / 56.04 / 96.56 / 92.86 / 88.94 / 84.89 / 80.51
Normal / 56.00 / 96.66 / 92.99 / 89.11 / 85.14 / 80.84
TNA#9 / Tumor / 44.35 / 95.27 / 91.79 / 87.72 / 83.16 / 77.97
Normal / 43.60 / 95.10 / 91.66 / 87.28 / 82.08 / 75.97
TNA#10 / Tumor / 38.03 / 95.93 / 91.03 / 85.26 / 78.71 / 71.31
Normal / 53.84 / 96.60 / 93.22 / 89.56 / 85.72 / 81.41
TNA#11 / Tumor / 41.50 / 93.26 / 88.94 / 84.32 / 79.17 / 73.43
Normal / 42.81 / 92.53 / 87.82 / 82.76 / 77.17 / 71.12
TNA#12 / Tumor / 62.80 / 95.02 / 92.15 / 88.91 / 85.42 / 81.66
Normal / 75.04 / 95.40 / 92.75 / 89.95 / 87.05 / 84.03
TNA#13 / Tumor / 42.67 / 93.77 / 89.95 / 85.32 / 79.99 / 74.06
Normal / 43.45 / 93.89 / 90.28 / 85.83 / 80.59 / 74.64
TNA#14 / Tumor / 61.29 / 95.11 / 92.00 / 88.58 / 84.93 / 81.00
Normal / 62.28 / 94.92 / 92.30 / 89.37 / 86.03 / 82.25
TNA#15 / Tumor / 49.61 / 94.82 / 90.90 / 81.75 / 76.81 / 66.45
Normal / 41.63 / 94.69 / 90.24 / 78.67 / 72.40 / 59.81
TNA#16 / Tumor / 54.89 / 95.44 / 92.95 / 85.88 / 81.17 / 70.20
Normal / 64.16 / 95.49 / 93.44 / 88.84 / 85.93 / 78.70

Table S2.Summary of depth and coverage in target capture sequencing for validation

Sample / Fold death of coverage / 1× (%) / 5× (%) / 10× (%) / 15× (%) / 20× (%)
TNA#1-T / 398.70 / 97.92 / 97.10 / 96.55 / 95.80 / 95.19
TNA#1-N / 190.14 / 96.00 / 91.39 / 87.58 / 84.09 / 81.46
TNA#2-T / 72.12 / 95.71 / 91.52 / 86.52 / 80.07 / 74.98
TNA#2-N / 250.58 / 96.58 / 92.99 / 89.63 / 86.15 / 83.78
TNA#3-T / 167.75 / 97.32 / 95.84 / 94.30 / 92.07 / 90.25
TNA#3-N / 315.61 / 96.78 / 93.80 / 91.02 / 88.18 / 85.96
TNA#4-T / 95.23 / 96.26 / 94.30 / 91.60 / 87.60 / 84.03
TNA#4-N / 256.71 / 96.32 / 92.49 / 88.93 / 85.56 / 83.21
TNA#5-T / 67.64 / 94.95 / 90.63 / 85.46 / 78.49 / 73.33
TNA#5-N / 350.07 / 93.20 / 86.60 / 81.86 / 77.93 / 75.23
TNA#6-T / 42.81 / 93.51 / 86.02 / 77.98 / 68.06 / 60.73
TNA#6-N / 206.33 / 93.97 / 88.61 / 84.86 / 81.45 / 78.95
TNA#7-T / 135.28 / 96.63 / 94.65 / 92.37 / 89.16 / 86.40
TNA#7-N / 92.46 / 81.52 / 65.46 / 56.68 / 49.62 / 45.18
TNA#8-T / 285.39 / 97.68 / 96.89 / 96.23 / 95.10 / 94.22
TNA#8-N / 62.80 / 94.18 / 86.89 / 80.28 / 73.12 / 67.95
TNA#9-T / 18.92 / 86.51 / 81.43 / 75.84 / 72.65 / 69.80
TNA#9-N / 68.57 / 96.13 / 91.78 / 86.37 / 78.80 / 72.96
TNA#10-T / 71.70 / 95.47 / 91.48 / 86.85 / 80.88 / 76.10
TNA#10-N / 324.47 / 96.46 / 92.80 / 89.22 / 85.64 / 83.24
TNA#11-T / 250.22 / 97.84 / 96.96 / 96.24 / 95.17 / 94.34
TNA#11-N / 105.56 / 90.36 / 80.46 / 73.33 / 66.95 / 62.72
TNA#12-T / 260.35 / 97.70 / 96.99 / 96.22 / 95.27 / 94.45
TNA#12-N / 24.55 / 81.06 / 61.44 / 48.53 / 36.86 / 30.31
TNA#13-T / 67.14 / 97.58 / 94.28 / 90.55 / 85.49 / 80.87
TNA#13-N / 211.92 / 97.71 / 96.31 / 94.94 / 92.98 / 91.40
TNA#14-T / 63.78 / 95.28 / 91.08 / 86.08 / 79.01 / 73.63
TNA#14-N / 80.43 / 84.85 / 69.39 / 60.72 / 52.74 / 47.75
TNA#15-T / 101.99 / 95.99 / 93.22 / 89.72 / 84.83 / 81.25
TNA#15-N / 69.06 / 93.05 / 84.88 / 77.26 / 69.49 / 64.20
TNA#16-T / 126.51 / 96.44 / 94.66 / 92.32 / 88.80 / 86.09
TNA#16-N / 92.19 / 87.90 / 76.34 / 68.88 / 62.40 / 58.32

1

Table S3.Validation results using target capture sequencing and Sanger sequencing

Gene / Position / Exome
sequencing / Target capture
sequencing / Sanger
sequencing / Validation
ADAMTS16 / chr5:5187877 / Positive / Positive / Positive / O
AKAP10 / chr17:19823350 / Positive / Positive / Positive / O
AKAP9 / chr7:91724351 / Positive / Positive / Positive / O
AKT2 / chr19:40747961 / Positive / Positive / Positive / O
AQP12B / chr2:241622103 / Positive / - / Positive / O
ARHGEF12 / chr11:120348991 / Positive / Positive / Positive / O
ASPSCR1 / chr17:79954544 / Positive / - / Positive / O
BRD2 / chr6:32945545 / Positive / Positive / Positive / O
CASS4 / chr20:55027042 / Positive / Positive / Positive / O
CCT2 / chr12:69981309 / Positive / Positive / Positive / O
CD1A / chr1:158225052 / Positive / Positive / Negative / X
CDC27 / chr17:45234417 / Positive / Positive / Positive / O
CDC27 / chr17:45234419 / Positive / Positive / Positive / O
CHEK2 / chr22:29121233 / Positive / Positive / Positive / O
COL27A1 / chr9:117071744 / Positive / - / Positive / O
COL4A5 / chrX:107938522 / Positive / Positive / Positive / O
CPSF2 / chr14:92621561 / Positive / Positive / Negative / X
CSMD3 / chr8:113402923 / Positive / Positive / Positive / O
CSPP1 / chr8:68005800 / Positive / Positive / Positive / O
CTAGE4 / chr7:143882511 / Positive / - / Positive / O
CTNNB1 / chr3:41266113 / Positive / Positive / Positive / O
CUL3 / chr2:225365144 / Positive / Positive / Positive / O
CYP2F1 / chr19:41633977 / Positive / Positive / Negative / X
ERBB4 / chr2:212295795 / Positive / Positive / Positive / O
ERC1 / chr12:1399135 / Positive / Positive / Positive / O
GABRD / chr1:1959067 / Positive / Positive / - / O
GABRG1 / chr4:46053620 / Positive / Positive / - / O
GABRG1 / chr4:46099344 / Positive / Positive / - / O
GSTT2 / chr22:24325095 / Positive / - / Positive / O
HELZ / chr17:65105364 / Positive / Positive / Positive / O
HIST1H4K / chr6:27799008 / Positive / Positive / Negative / X
HIVEP3 / chr1:42045651 / Positive / Positive / Positive / O
HLA-B / chr6:31324057 / Positive / Positive / Positive / O
HOMER1 / chr5:78671893 / Positive / Positive / Positive / O
HRNR / chr1:152187437 / Positive / - / Positive / O
H1FOO / chr3:129262077 / Positive / - / Positive / O
JPH1 / chr8:75171665 / Positive / Positive / Positive / O
KIAA0895 / chr7:36373540 / Positive / Positive / Positive / O
LDHAL6A / chr11:18500358 / Positive / Positive / Positive / O
MBD2 / chr18:51686266 / Positive / Positive / - / O
MECP2 / chrX:153296461 / Positive / Positive / Positive / O
MLL4 / chr19:36222857 / Positive / - / Positive / O
MOSC1 / chr1:220970028 / Positive / - / Positive / O
MST1R / chr3:49924940 / Positive / Positive / Positive / O
MTRF1L / chr6:153323709 / Positive / Positive / Positive / O
NAALAD2 / chr11:89880587 / Positive / Positive / Positive / O
NBPF10 / chr1:145299932 / Positive / Positive / Positive / O
NDRG1 / chr8:134260154 / Positive / Positive / Positive / O
NOTCH2 / chr1:120611960 / Positive / - / Positive / O
NUP50 / chr22:45574280 / Positive / Positive / Positive / O
PABPC1 / chr8:101727750 / Positive / Positive / Positive / O
PARP4 / chr13:25021323 / Positive / Positive / - / O
PBRM1 / chr3:52643408 / Positive / Positive / Positive / O
PCDHB14 / chr5:140605086 / Positive / Positive / - / O (TNA#4)
PCDHB14 / chr5:140605086 / Positive / Positive / - / O (TNA#6)
PCDHB15 / chr5:140627155 / Positive / Positive / - / O
PHIP / chr6:79735874 / Positive / Positive / Positive / O
PIK3CA / chr3:178917478 / Positive / Positive / Positive / O
PLD5 / chr1:242271062 / Positive / Positive / Positive / O
POTEB / chr15:21071439 / Positive / - / Positive / O
PRAMEF1 / chr1:12853509 / Positive / Positive / Positive / O
PRRC1 / chr5:126860520 / Positive / Positive / Negative / X
PRSS38 / chr1:228033197 / Positive / - / Positive / O
PSPH / chr7:56084929 / Positive / Positive / Positive / O
PTPRC / chr1:198685877 / Positive / Positive / Positive / O
PTPRC / chr1:198723415 / Positive / Positive / - / O
RAD50 / chr5:131923749 / Positive / Positive / Positive / O
RECQL5 / chr17:73647273 / Positive / Positive / Positive / O
RFPL4A / chr19:56273285 / Positive / Positive / Positive / O
RIN3 / chr14:93118038 / Positive / - / Positive / O
RNF213 / chr17:78317090 / Positive / Positive / Positive / O
RPL19 / chr17:37360846 / Positive / Positive / Positive / O
SEL1L2 / chr20:13936724 / Positive / Positive / Positive / O
SLAIN2 / chr4:48381728 / Positive / Positive / Positive / O
SLC7A1 / chr13:30107113 / Positive / Positive / Positive / O
SOD2 / chr6:160103614 / Positive / Positive / Positive / O
SULF1 / chr8:70512849 / Positive / Positive / Positive / O
SYK / chr9:93639869 / Positive / - / Positive / O
SYNE2 / chr14:64554542 / Positive / Positive / Positive / O
TCEB3 / chr1:24083477 / Positive / Positive / Positive / O
TGFBR2 / chr3:30729914 / Positive / Positive / Positive / O
TMTC1 / chr12:29709865 / Positive / Positive / Positive / O
TP53BP1 / chr15:43748861 / Positive / Positive / Negative / X
TP53BP1 / chr15:43738724 / Positive / Positive / Positive / O
TPSD1 / chr16:1306523 / Positive / Positive / Positive / O
TROAP / chr12:49724304 / Positive / - / Positive / O
TSC1 / chr9:135778003 / Positive / Positive / Positive / O
UACA / chr15:70991933 / Positive / Positive / Positive / O
UNC93A / chr6:167728775 / Positive / - / Positive / O
USP29 / chr19:57641481 / Positive / Positive / Positive / O
VCX2 / chrX:8138284 / Positive / Positive / Positive / O
WAPAL / chr10:88259559 / Positive / Positive / Positive / O
WASH1 / chr9:16020 / Positive / Positive / Positive / O
XBP1 / chr22:29191396 / Positive / Positive / Positive / O
YTHDF1 / chr20:61833818 / Positive / Positive / Positive / O (TNA#8)
YTHDF1 / chr20:61833818 / Positive / Positive / Positive / O (TNA#10)
ZNF521 / chr18:22805549 / Positive / Positive / Positive / O

1

Table S4.Summary of validated somatic exonic mutations in EGFR/KRAS/ALK-negative lung adenocarcinomas

Patient / Mutation/Mb / Missense / Nonsense / Indel / Total
TNA#1 / 0.10 / 1 / 2 / 0 / 3
TNA#2 / 0.10 / 3 / 0 / 0 / 3
TNA#3 / 0.14 / 3 / 0 / 1 / 4
TNA#4 / 0.17 / 4 / 1 / 0 / 5
TNA#5 / 0.21 / 7 / 0 / 0 / 7
TNA#6 / 0.21 / 7 / 0 / 0 / 7
TNA#7 / 0.24 / 8 / 0 / 0 / 8
TNA#8 / 0.31 / 7 / 1 / 1 / 9
TNA#9 / 0.40 / 10 / 0 / 1 / 11
TNA#10 / 0.40 / 10 / 0 / 1 / 11
TNA#11 / 0.55 / 14 / 2 / 0 / 16
TNA#12 / 0.58 / 18 / 0 / 0 / 18
TNA#13 / 0.72 / 21 / 2 / 0 / 23
TNA#14 / 0.87 / 21 / 4 / 0 / 25
TNA#15 / 0.90 / 24 / 2 / 0 / 26
TNA#16 / 0.94 / 26 / 2 / 0 / 28

1

Table S5.Somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma exomes

missense / indel / nonsense / missense/
nonsense
Gene / COSMIC v.65 / TNA#1 / TNA#2 / TNA#3 / TNA#4 / TNA#5 / TNA#6 / TNA#7 / TNA#8 / TNA#9 / TNA#10 / TNA#11 / TNA#12 / TNA#13 / TNA#14 / TNA#15 / TNA#16
Represented in Figure 1
ERBB4 / O / p.V840I
PIK3CA / O / p.G118D
AKT2 / - / p.D153Y
TSC1 / - / p.Q793*
CTNNB1 / O / p.S37C
TGFBR2 / O / p.R504W
SETD2 / - / p.V1576F
PBRM1 / - / p.E830*
MBD2 / - / p.E373K
MECP2 / O / p.G273V
CHEK2 / - / p.R191G
CDC27 / O / p.A273G / p.I235T
PARP4 / O / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / p.I1039T / 0 / 0 / 0 / 0
CUL3 / - / p.Q516*
SOD2 / - / p.K194E
GABRD / - / p.D174E
GABRG1 / - / p.D43N / p.T318S
SYNE2 / - / p.E3880*
NDRG1 / - / p.L257fs
TFG / - / p.E240*
CSMD3 / - / p.K1928N
SYK / - / 0 / 0 / p.A400S / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
PTPRC / - / p.T1176M / p.T453M
ASPSCR1 / - / p.L252Q
YTHDF1 / - / p.I492V / p.I492V
PCDHB14 / - / 0 / 0 / 0 / p.Y670S / 0 / p.Y670S / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
PCDHB15 / - / 0 / 0 / 0 / 0 / 0 / p.Y670S / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
Others
BDP1 / nonsense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
GSTT2 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
PAPPA / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
ZNF107 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
MST1R / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
HLA-B / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
NR1H2 / 0 / 0 / indel / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
AQP12B / 0 / 0 / 0 / missense / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
NBPF14 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
VCX2 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
CTAGE4 / 0 / 0 / 0 / 0 / missense / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
NBPF10 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
LILRB4 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
PLD5 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
MCTP1 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
WASH1 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
EXOC2 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
RIN3 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
TUBB2C / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
TPSD1 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
NOTCH2 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
ZNF285 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
TUBA3D / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
TROAP / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
H1FOO / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
RFPL4A / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
SNRNP200 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / nonsense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
TPSAB1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
MICB / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
MUC5AC / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
C6orf134 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
KEL / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0
ROBO4 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0
NBPF1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0
SLC6A19 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0
ATP8B1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0
UNC93A / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0
DMTF1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0
PDIA2 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0 / 0
JPH1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0
PRAMEF1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0
OR1L4 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0
HOXD9 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / indel / 0 / 0 / 0 / 0 / 0 / 0
TEKT4 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0
MTRF1L / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / missense / 0 / 0 / 0
MLL4 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0
TBC1D26 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0
POTEB / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0 / 0
ZNF521 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0
USP29 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0
GOLGB1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0
SLC7A1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0
UACA / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0
SULF1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0
OR51E2 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0
COL27A1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0
PABPC1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0
OR10C1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0
C4orf41 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0
AP3M1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0
HLA-DQB2 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0
CCT2 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / nonsense / 0 / 0 / 0 / 0 / 0
NFKBID / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0 / 0
C11orf41 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0
HUWE1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0
PLXNA2 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0
TANC2 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0
PHIP / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0
NAALAD2 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0
MOV10L1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0
EXOSC9 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0
HLA-DRB1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0
PLA2G3 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0
RNASEH2A / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0 / 0
MUC16 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / missense / 0 / 0 / 0
COL4A5 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0
TMTC1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0
LILRB2 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0
ADAMTS7 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0
GFRA1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0
CSPP1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0
OSGEP / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0
CASS4 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0
DNPEP / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0
TMEM86A / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0
CXorf58 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0
CRYBA4 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / nonsense / 0 / 0 / 0
ANKRD31 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0 / 0
APOB / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
FER1L6 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
AKAP9 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
OR6K6 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
C7orf10 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
TP53BP1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
ZSWIM5 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
AKAP10 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
SEL1L2 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
WAPAL / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
ZC3H18 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
HOMER1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
KIAA0895 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
SGCE / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
CDC23 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
SLAIN2 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
RAB41 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
TCEB3 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0 / 0
SHB / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / nonsense / 0 / 0
HRNR / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
ADCY8 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
GRIA2 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
RNF213 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
MYO10 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
HELZ / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / nonsense / 0
PRSS38 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
KARS / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
GPA33 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
RBM46 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
ERC1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
KLHL22 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
MOSC1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
RPL19 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
FANK1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / nonsense / 0
CC2D2B / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
SLC2A13 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
ZNF488 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
FRG1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
ARHGEF12 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
SRP14 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
RECQL5 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
FOXK2 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
NUP50 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense / 0
USH2A / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
SVEP1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
ADAMTS16 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
HIVEP3 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / nonsense
AMOT / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
OR2G2 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
PTPN5 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / nonsense
RAD50 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
PDE5A / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
TRDMT1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
CNGA1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
C12orf41 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
C14orf39 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
KIAA0355 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
XBP1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
USP39 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
MAGEA10 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
LCE1B / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
BRD2 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
LDHAL6A / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
SMCR8 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
PSPH / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
ME1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense
CCDC66 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / indel
MTCH2 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / missense

1

Table S6.Mutated genes and loci information in EGFR/KRAS-negative lung adenocarcinoma.

Gene / Mutation frequency in our set (N=16) / Mutation frequency in independent set (N=40) / Mutation frequency in TCGA set
(N=14) / Total (N) / AA substitution / COSMIC v.65 / No. of damage algorithms
TP53 / - / 6/40 / 2/14 / 8/70 / K93R
122_122del
Y124C
C203F
G206S
R209W
E219*
G295A / O
O
O
O
O
O
O
O / 4/4
NA
4/4
4/4
4/4
4/4
2/4
4/4
SETD2 / 1/16 / 2/40 / 1/14 / 4/70 / R839*
V1576F
Q1981*
K2067* / -
-
-
- / 1/2
3/3
2/2
0/1
CSMD3 / 1/16 / 1/40 / 2/14 / 4/70 / P667S
M1440I
K1928N
Y2028C / O
-
-
- / 3/4
3/4
3/4
3/4
PTPRC / 2/16 / 1/40 / - / 3/70 / Y444N
T453M
T1176M / O
-
- / 3/4
3/4
4/4
SYNE2 / 1/16 / 2/40 / - / 3/70 / 2579_2580del
E3880*
E3903K / -
-
O / NA
NA
3/4
GRIN2A / - / 3/40 / - / 3/70 / L307Q
N886S
T1069M / -
O
O / 3/4
0/4
3/4
CDH10 / - / 2/40 / 1/14 / 3/70 / E171K
D315H
R472C / O
O
O / 4/4
1/4
4/4
ERBB2 / - / - / 3/14 / 3/70 / E740delinsEAYVM (2)
G746delinsVC / -
O / NA
NA
SMAD4 / - / - / 3/14 / 3/70 / S242*
R361S
D493N / -
O
O / 1/2
4/4
3/4
CDC27 / 2/16 / - / - / 2/70 / I235T
A273G / -
O / 4/4
3/4
GABRG1 / 2/16 / - / - / 2/70 / D43N
T318S / -
- / 2/4
3/4
YTHDF1 / 2/16 / - / - / 2/70 / I492V (2) / - / 4/4
PCDHB14 / 2/16 / - / - / 2/70 / Y670S (2) / - / 2/3
MECP2 / 1/16 / - / 1/14 / 2/70 / R168L
G273V / -
O / 2/3
3/3
NRAS / - / 2/40 / - / 2/70 / Q61H
Q61K / O
O / 2/4
3/4
MET / - / - / 2/14 / 2/70 / Y1021*
1027_1028del / -
- / 2/2
NA
EPHA2 / - / 2/40 / - / 2/70 / P147L
P278S / O
O / 4/4
2/4
CHD2 / - / 2/40 / - / 2/70 / S391fs
splicing(c.5153) / -
O / NA
NA
ERBB4 / 1/16 / - / - / 1/70 / V840I / O / 4/4
PIK3CA / 1/16 / - / - / 1/70 / G118D / O / 2/3
AKT2 / 1/16 / - / - / 1/70 / D153Y / - / 4/4
TSC1 / 1/16 / - / - / 1/70 / Q793* / - / 2/2
CTNNB1 / 1/16 / - / - / 1/70 / S37C / O / 4/4
TGFBR2 / 1/16 / - / - / 1/70 / R504W / O / 4/4
PBRM1 / 1/16 / - / - / 1/70 / E830* / - / 2/2
MBD2 / 1/16 / - / - / 1/70 / E373K / - / 4/4
CHEK2 / 1/16 / - / - / 1/70 / R191G / - / 3/4
PARP4 / 1/16 / - / - / 1/70 / I1039T / O / 4/4
CUL3 / 1/16 / - / - / 1/70 / Q516* / - / 2/2
SOD2 / 1/16 / - / - / 1/70 / K194E / - / 3/4
GABRD / 1/16 / - / - / 1/70 / D174E / - / 4/4
NDRG1 / 1/16 / - / - / 1/70 / L257fs / - / NA
TFG / 1/16 / - / - / 1/70 / E240* / - / 1/1
SYK / 1/16 / - / - / 1/70 / A400S / - / 4/4
ASPSCR1 / 1/16 / - / - / 1/70 / L252Q / - / 3/3
PCDHB15 / 1/16 / - / - / 1/70 / Y670S / - / 3/3
NUP98 / - / 2/40 / 1/14 / 3/70 / G716C
S1294C
A1596V / -
O
- / 4/4
3/3
1/3
USP39 / 1/16 / 2/40 / - / 3/70 / D119Y
Q563*
329_329del / -
O
- / 3/3
0/1
NA
SLITRK2 / - / 2/40 / - / 2/70 / S276fs
N554H / O
O / NA
3/4
TAF1 / - / 2/40 / - / 2/70 / R1442W
Y1194D / O
O / 4/4
4/4
UNC13B / - / 2/40 / - / 2/70 / T638I
G500D / O
O / 3/4
4/4
FN1 / - / 2/40 / - / 2/70 / D920G
V2171fs / -
O / 4/4
NA
NAV2 / - / 2/40 / - / 2/70 / R496L
S1413R / O
O / 4/4
4/4
NUP133 / - / 2/40 / - / 2/70 / S189R
1050_1051del / O
- / 4/4
NA
CDC42BPG / - / 2/40 / - / 2/70 / G358E
P925T / O
O / 3/4
3/4
COL25A1 / - / - / 2/14 / 2/70 / R375Q
D289N / O
O / 3/3
2/3
GRM1 / - / - / 2/14 / 2/70 / S228F
S207C / -
- / 4/4
4/4
ACACB / - / - / 2/14 / 2/70 / S2314Y
L2182fs / -
- / 2/3
NA
ANKHD1-EIF4EBP3 / - / - / 2/14 / 2/70 / D286N
1532_1532del / -
- / 2/3
NA
ARSD / - / - / 2/14 / 2/70 / C583Y
splicing(c.1136) / -
- / 3/4
NA
CRIPAK / - / - / 2/14 / 2/70 / R430C
153_163del / O
O / 2/3
NA
GRID1 / - / - / 2/14 / 2/70 / R462H
K694N / -
- / 4/4
3/4
HMCN1 / - / - / 2/14 / 2/70 / A2271V
G3137* / -
- / 3/4
2/2
MST1 / - / - / 2/14 / 2/70 / 406_407del
R535G / -
- / NA
3/4
SPAM1 / - / - / 2/14 / 2/70 / R211W
W339C / -
- / 4/4
4/4
TDP2 / - / - / 2/14 / 2/70 / W284L
L342P / -
- / 4/4
4/4
GOLGB1 / 1/16 / 1/40 / - / 2/70 / E85D
V2705L / -
O / 3/4
3/4
DNPEP / 1/16 / 1/40 / - / 2/70 / P422L
G102W / -
O / 3/4
4/4

Table S7.Sequences of molecular inversion probes (MIPs)

A preview of Table S7 is shown below.

The full version is available at ‘Supple_Tables.xls’. –‘Table_S7’.

Table S8.Sequences of primers used for Sanger sequencing.

A preview of Table S8 is shown below.

The full version is available at ‘Supple_Tables.xls’. –‘Table_S8’.

References for exomeanalysis

Novoalign ( alignment of sequencing data

SAMTools–for manipulating Sequence Alignment/Map (SAM) format

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R. 2009. The Sequence Alignment/Map format and SAMtools. Bioinformatics25(16): 2078-2079.

Picard ( manipulationof aligned sequencing data (FixMateInformation, MarkDuplication)

GATK (Genome Analysis Toolkit; version 1.4-21)–for detection of genetic variants in exome data

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M et al. 2010. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome research20(9): 1297-1303.

DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, Philippakis AA, del Angel G, Rivas MA, Hanna M et al. 2011. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nature genetics43(5): 491-498.

muTect–for detection of genetic variants in exome data

Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, Gabriel S, Meyerson M, Lander ES, Getz G. 2013. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nature biotechnology31(3): 213-219.

VarScan–for detection of genetic variants in exome data

Koboldt DC, Chen K, Wylie T, Larson DE, McLellan MD, Mardis ER, Weinstock GM, Wilson RK, Ding L. 2009. VarScan: variant detection in massively parallel sequencing of individual and pooled samples. Bioinformatics25(17): 2283-2285.

ANNOVAR–for functional annotation of genetic mutations

Wang K, Li M, Hakonarson H. 2010. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic acids research38(16): e164.

Polyphen2–for prediction of protein consequences of genetic mutations

Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. 2010. A method and server for predicting damaging missense mutations. Nature methods7(4): 248-249.

SIFT (Sorting Intolerant From Tolerant) –for prediction of amino acid changes that affect protein function

Ng PC,Henikoff S. 2003. SIFT: Predicting amino acid changes that affect protein function.Nucleic acids research31(13): 3812-3814.

LRT (Likelihood Ratio Test) –todistinguish deleterious mutations from a large number of variants

S. Chun, J.C. Fay.2009. Identification of deleterious mutations within three human genomes. Genome Research19(9): 1553-1561.

MutationTaster–for discovery of potential damaging mutations

Schwarz JM, Rödelsperger C, Schuelke M, Seelow D. 2010.MutationTaster evaluates disease-causing potential of sequence alterations.Nature methods7(8): 575-576.

1